Neoplastic disease states in humans are recognized throughout the world as being serious and oftentimes life-threatening conditions. These neoplastic diseases, which are characterized by rapidly-proliferating cell growth, have been and continue to be the subject of worldwide research efforts directed toward the identification of therapeutic agents which are effective in the treatment of patients suffering therefrom. Effective therapeutic agents can be characterized as those which prolong the survivability of the patient, which inhibit the rapidly-proliferating cell growth associated with the neoplasm, or which effect a regression of the neoplasm. Research in this area is primarily focused toward identifying agents which would be therapeutically effective in humans. Typically, compounds are tested for antineoplastic activity in small mammals, such as mice, in experiments designed to be predictive of antineoplastic activity not only in those animals but also in humans against specific neoplastic disease states.
Radiosensitizing agents, also known as radiosensitizers, are defined as agents which sensitize cells or organisms to the deleterious cellular effects of exposure to ionizing or nonionizing radiation. These deleterious cellular effects include disruption in cellular function, cell death, and the like. These agents, administered prior to or during exposure, would enhance the severity of deleterious cellular effects to neoplasms caused by exposure to ionizing or nonionizing radiation administered during cancer radiation therapy.
Furthermore, certain radiosensitizing agents provide a sensitization for deleterious cellular effects in cancer cells caused by certain DNA-reactive agents such as cisplastin, cyclophosphamide, diethylnitrosoamine, benzo(a)pyrene, carboplatin, doxorubicin, mitomycin-C and the like. Many of these DNA-reactive agents are chemotherapeutic agents useful in cancer therapy. Radiosensitizing agents are useful in enhancing the severity of deleterious cellular effects in cancer cells caused by exposure to these DNA-reactive agents, such as during cancer therapy with DNA-reactive chemotherapeutic agents.
Ribonucleotide reductase inhibitors, as a class, are known to be effective inhibitors of DNA repair in mammalian cells, see Ben-Hur, E., et al., Photochem. Photobiol. 13: 337-345 (1971); Francis, A. A., et al., Biochim. Biophys. Acta 563: 385-392 (1979); and Snyder, R. D., Cell Biol. Toxicol. 1:81-94 (1984). Specifically, certain 2'-halomethylidene derivatives, such as (E)-2'-deoxy-2'-fluoromethylidenecytidine, are well known as effective antineoplastic agents; see European Patent Application Publication No. 0 372 268, published Jun. 13, 1990. These 2'-halomethylidene derivatives, such as (E)-2'-deoxy-2'-fluoromethylidenecytidine are ribonucleotide reductase inhibitors with potent antiproliferative and antitumor activity which are also useful in the treatment of patients suffering from a variety of neoplastic disease states. Furthermore, a recent report demonstrates that the compound 2',2'-difluorodeoxycytidine provides a radiosensitizing effect in a murine mammary tumor cell line; Rockwell, S., Oncology Res. 4:151-155 ( 1992).
Applicant has discovered that treating a patient afflicted with certain neoplastic disease states prior to or during radiation or chemotherapy therapy with (E)-2'-deoxy-2'-fluoromethylidenecytidine will provide a sensitizing effect. A sensitizing effect is achieved when a greater antineoplastic effect results with a conjunctive therapy than use of either drug or therapy alone. Specifically, (E)-2'-deoxy-2'-fluoromethylidenecytidine provides a selective sensitization for deleterious cellular effects in cancer cells.